Hydrogels can be characterized by three-dimensional networks of polymer chains that can be reversibly deformed. They absorb polar solvents such as water and they find applications in, for example, medical applications including bone transplants and tissue adhesives, drug delivery systems, pharmaceuticals and in water management.
Hydrogels can occur in the cross-linked form or in the uncross-linked form. Cross-linking usually provides stiffer gels due to strong increase of the molecular weight. Cross-linking can be achieved chemically by the formation of covalent bonds or physically by the formation of, e.g., hydrogen bonds or ionic interactions. Obviously, cross-linking can also be achieved by both chemical and physical means.
Chemical cross-linking of hydrophilic polymers is a general and often applied route to obtain hydrogels. In order to be able to administer or process these gels, prepolymers are dissolved in water and are then polymerized resulting in (in situ) hydrogel formation. Hydrogellation procedures are often based on the use of acrylic or methacrylic macromonomers that are not preferred in (biomedical) applications, because of their inherent toxicity and because they usually require a potentially hazardous initiator for polymerization. Moreover, cross-linked hydrogels lack reversibility and are limited in their degradation behavior, as poly(acrylates) and poly(methacrylates) are not biodegradable.
For example, U.S. Pat. No. 5,410,016, incorporated by reference, discloses hydrogels based on copolymers of poly(ethylene glycol) with poly(DL-lactide) containing pendant acrylate functions that are cross-linked in situ.
WO 01/44307, incorporated by reference, discloses hydrogels based on polyvinyl alcohol modified with pendant acrylate and methacrylate groups that are chemically cross-linked in situ. Hence, in both patent documents, an irreversible cross-linked hydrogel is obtained by starting from water-processable prepolymers that contain reactive groups. Because a relative high level of cross-links is needed to gel these materials, the resulting hydrogels are rigid and lack beneficial elastic behavior.
U.S. Pat. No. 8,673,286, incorporated by reference, discloses branched 4-arm poly(ethyleneglycol) materials end-functionalized with DOPA-groups (3,4-dihydroxyphenyl alanine), which aqueous formulations upon oxidative cross-linking result in adhesive hydrogels with 15-30 wt % solids content.
U.S. Patent Publication 2014/0113989, incorporated by reference, discloses branched 4-arm poly(ethyleneoxide)-poly(propylene oxide) copolymers materials end-functionalized with DOPA-groups that display negative swelling hydrogels upon oxidative cross-linking.
Messersmith et al., Chem. Comm. 47:7497, 2011, incorporated by reference, discloses a pH-responsive hydrogel resulting from a cross-linked polymer made by reacting a branched 4-arm poly(ethyleneglycol) materials end-functionalized with DOPA-groups with bifunctional boronic acid moieties. Clearly, this approach needs two different ingredients in a specific ratio to obtain a gel. Moreover, this system is only gelled at an alkaline pH of 9 and boronic acid derivatives are needed, which makes the biomedical application of this hydrogel system difficult due to the high pH and the increased concerns about the detrimental health effects of boric acid derivatives. The resulting hydrogels are tacky and, therefore, obviously demonstrate self-adhesive behavior.
WO 99/07343, incorporated by reference, discloses thermally reversible hydrogels intended for uses in drug delivery applications that are based on a hydrophilic polyethylene glycol block and hydrophobic PLLA (poly-L-lactic acid) blocks. The gelling is governed by the presence of the crystalline hard blocks formed by the PLLA. The presence of the crystalline PLLA-blocks limits the mechanical properties and the biodegradation of these materials to a great extent.
In general, “supramolecular chemistry” is understood to be the chemistry of physical or non-covalent, oriented, multiple (at least two), co-operative interactions. For instance, a “supramolecular polymer” is an organic compound that has polymeric properties, for example, with respect to its rheological behavior due to specific and strong secondary interactions between the different molecules. These physical or non-covalent supramolecular interactions contribute substantially to the properties of the resulting material.
Supramolecular polymers comprised of (macro)molecules that bear hydrogen bonding units can have polymer properties in bulk and in solution because of the hydrogen bridges between the molecules. Sijbesma et al. (U.S. Pat. No. 6,320,018 and Science 278:1601, 1997, both incorporated by reference) have shown that in cases where a self-complementary quadruple hydrogen bonding unit (4H-unit) is used, the physical interactions between the molecules become so strong that polymers with much improved material properties can be prepared.
WO 2006/118460, incorporated by reference, discloses supramolecular hydrogel materials comprising water gellants that are comprised of hydrophilic polymers to which at least two 4H-units are covalently attached via urethane-alkyl moieties. However, it appeared that these hydrogel materials are insufficient in strength for several applications and their viscosity is too high at biomedically relevant temperatures to allow administration via liquid processing techniques like injection through a syringe.
EP 1.972.661 A1, incorporated by reference, discloses supramolecular hydrogels that comprise 4H-units, together with urea bonding-motifs in a hydrophilic polymer. These hydrogels are thermo-reversible due to their supramolecular nature. However, their reversible nature may also result in dissolving of the gel when an excess amount of water is present such as inside the body.
Dankers et al., Adv. Healthcare Mat. 3:87, 2014, incorporated by reference, discloses that a hydrogel of a specific embodiment of EP 1.972.661 A1, consisting of a poly(ethyleneglycol) of 10,000 Da with 4H-unit end groups, can be rendered injectable only when dissolved in strongly basic aqueous solution with a pH higher than 8.5, which is not favored for biomedical applications. Moreover, the resulting hydrogel has very limited elastic strength.
Dankers et al., Adv. Mater. 24:2703, 2012, incorporated by reference, discloses transient networks based on bifunctional supramolecular polymers consisting of polyethylene glycol which is end-functionalized with 4H-units. The 4H-units are shielded by hydrophobic alkylene groups comprising a urea moiety for lateral hydrogen bonding. The transient networks are only formed by supramolecular interactions between the polymer chains.
Hirschberg et al., Chem. Eur. J. 9:4222, 2003, incorporated by reference, discloses mono- and bifunctional compounds comprising one or two 4H-units, respectively. Some of the bifunctional compounds have been shown to form polymers in apolar solvents by intermolecular supramolecular interactions only.
Kieltyka et al., J. Am. Chem. Soc. 135:11159, 2013, incorporated by reference, discloses the bifunctional supramolecular polymers as Dankers et al., Adv. Mater. 24:2703, 2012, as well as the corresponding monofunctional supramolecular polymers. Transient networks based on mixtures of the bifunctional and monofunctional supramolecular polymers are only formed by supramolecular interactions between the polymer chains.
Ramaekers et al., Macromolecules 47:3823, 2014, incorporated by reference, discloses chiral derivatives of the bifunctional supramolecular polymers as Dankers et al., Adv. Mater. 24:2703, 2012. In water, these polymers may form helical fibers by supramolecular interactions between the polymer chains.
Lee-Wang et al., Macromol. Symp. 296:229, 2010, incorporated by reference, discloses telechelic PPG-PEG-PPG polymers, which end-functionalized with 4H-units. These polymers are reported to have a low solubility in water and do not form hydrogels, although associating behavior of the 4H-units was observed.
Because of the shortcomings of state-of-the-art hydrogels, there is a need for synthetic polymers that are injectable, can gel water upon command, need only a limited amount of cross-links to gel, are highly elastic, are able to dissipate energy, and display self-healing behavior. In addition, it is desired that hydrogels can be tuned with respect to their mechanical properties to be able to meet the requirements of specific applications. Also, it would be advantageous to be able to make biodegradable reversible hydrogels.